scholarly journals The Role of Thymoquinone in Mitigating Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Rats: Targeting the CHOP-1/JNK/P38 MAPK, NFκB/TNF-α/IL-10, and Bax/Bcl-2/Caspase-3 Signalling Pathways

2021 ◽  
Vol 69 (1) ◽  
pp. 1-9
Author(s):  
Rania Elsayed Hussein ◽  
Laila Ahmed Rashed ◽  
Basma Emad Aboulhoda ◽  
Ghada Mahmoud Abdelaziz ◽  
Ebtehal Gamal Abdelhady ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
P38 Mapk ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Mitogen Activated Protein Kinase ◽  
Lipid Peroxidation Product ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Bax Gene

The present study was conducted to evaluate the effect of thymoquinone (TQ) on hepatocellular carcinoma (HCC) in rats. Our study has reported that TQ treatment of experimentally-induced HCC results in the up-regulation of the Jun-N-terminal kinase and p38 mitogen activated protein kinase pathway (JNK/p38 MAPK) and the enhancement of anti-inflammatory, anti-oxidant, and pro-apoptotic machineries. TQ resulted in a significant decrease in the levels of nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB), tumor necrosis factor-α (TNF-α), and a significant increase in the anti-inflammatory interleukin-10 (IL-10). The pro-apoptotic effect of TQ was demonstrated through stimulating the apoptotic Bcl-2-associated X (Bax) gene and inhibiting the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene together with increasing the level of caspase 3 and up-regulating the C/EBP homologous protein (CHOP-1) gene expression. TQ treatment also enhanced the activity of the ROS scavenger, superoxide dismutase (SOD), and decreased the level of the lipid peroxidation product malondialdehyde (MDA). TQ-dependent suppression of HCC was associated with the up-regulation of JNK/p38 MAPK, enhanced CHOP-1 expression, and subsequently increased Bax gene expression.

Analyzing the anti-ischemia–reperfusion injury effects of ginsenoside Rb1 mediated through the inhibition of p38α MAPK

2016 ◽  
Vol 94 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Gonghao Li ◽  
Wenhao Qian ◽  
Changyun Zhao
Keyword(s):  
P38 Mapk ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Ginsenoside Rb1 ◽  
Group I ◽  
Tnf Α ◽  
P38α Mapk

Recent studies have demonstrated that ginsenoside Rb1 protects the myocardium from ischemia–reperfusion (I/R) injury. However, the precise mechanisms for this protection have not been determined. This study aimed to determine whether the attenuation of I/R-induced myocardial injury by ginsenoside Rb1 (GS Rb1) is due to inhibition of p38α mitogen-activated protein kinase (MAPK). Sprague–Dawley rats were distributed among 6 treatment groups: sham group; I/R group; p38 MAPK inhibitor SB203580 group (SB + I/R); GS Rb1 group (GS + I/R); p38 MAPK agonist anisomycin group (Ani + I/R); and the GS Rb1 + Ani group (GS + Ani + I/R). All of the anaesthetized rats, except those in the sham group, underwent an open-chest procedure that involved 30 min of myocardial ischemia followed by 2 h of reperfusion. Myocardial infarction size (MIS), caspase-3 activity, and levels of the cytokine tumor necrosis factor alpha (TNF-α) in the myocardium were monitored. The expressions of p38α MAPK, caspase-3, and TNF-α in the myocardium were assayed. GS Rb1 reduced MIS and attenuated caspase-3 activity and the levels of TNF-α in the myocardium. Protein expression of total p38α MAPK was not significantly altered. In the Ani + I/R and I/R groups, the levels of phospho-p38α MAPK were significantly increased compared with the sham group, and these increased levels were reduced with GS Rb1. Hemodynamic parameters were not significantly different between the GS + I/R and SB + I/R groups. GS Rb1 exerts an anti-apoptotic effect that protects against I/R injury by inhibiting p38α MAPK phosphorylation, suggesting that GS Rb1-mediated protection requires the inhibition of p38α MAPK.

scholarly journals Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-α signaling

2007 ◽  
Vol 31 (2) ◽  
pp. 343-351 ◽  
Author(s):  
Cindy Zer ◽  
George Sachs ◽  
Jai Moo Shin
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Proinflammatory Cytokines ◽  
Quantitative Polymerase Chain Reaction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Gene Expressions ◽  
Tnf Α ◽  
Induced Genes ◽  
Sb 203580

Inhibition of p38 MAPK suppresses the expression of proinflammatory cytokines such as TNF-α and IL-1β in macrophages and fibroblast-like synoviocytes (FLS). However, there have been no genomewide studies on the gene targets of p38 MAPK signaling in synoviocytes. Microarray technology was applied to generate a comprehensive analysis of all genes regulated by the p38 MAPK signaling pathway in FLS. Gene expression levels were measured with Agilent oligonucleotide microarrays. Four independent sets of mRNA modulated by TNF-α and vehicle were used to measure the change of gene expression due to TNF-α, and three experiments were done to ascertain the effect of SB-203580, a p38 MAPK inhibitor, on TNF-α-induced genes. Microarray data were validated by RT-quantitative polymerase chain reaction. One hundred forty-one significantly expressed genes were more than twofold upregulated by TNF-α. Thirty percent of these genes were downregulated by the p38 inhibitor SB-203580, whereas 67% of these genes were not significantly changed. The SB-203580-inhibited genes include proinflammatory cytokines such as interleukins and chemokines, proteases including matrix metallopeptidases, metabolism-related genes such as cyclooxygenases and phosphodiesterase, genes involved in signal transduction, and genes encoding for transcription factors, receptors, and transporters. Approximately one-third of the TNF-α-induced genes in FLS are regulated by the p38 MAPK signal pathway, showing that p38 MAPK is a possible target for suppressing proinflammatory gene expressions in rheumatoid arthritis.

scholarly journals Effect of camphor on biochemical factors and gene expression of antioxidant enzymes, inflammatory and apoptotic factors against gentamicin-induced nephrotoxicity in rats

2020 ◽  
Vol 10 (3) ◽  
pp. e21-e21
Author(s):  
Ali Valibeik ◽  
Negar Naderi ◽  
Abdolhakim Amini ◽  
Niloufar Tavakoli Dastjerd ◽  
Sobhan Rahimi Monfared ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antioxidant Enzymes ◽  
Structural Changes ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Inflammatory Factors ◽  
Histopathological Changes ◽  
Necrosis Factor Alpha ◽  
Treatment Groups ◽  
Tnf Α

Introduction: Camphor is a natural antioxidant with anti-inflammatory and tissue repair properties. Nephrotoxicity is the most important side effect of gentamicin (GEM) administration. Therefore, investigating the effect of natural antioxidants can resolve this complication. Objectives: We aimed to assay the effect of camphor on biochemical factors and gene expression of antioxidant enzymes (catalase [CAT], glutathione peroxidase [GPX]) and inflammatory markers (tumor necrosis factor-alpha [TNF-α], nuclear factor kappa-B [NF-κB], interleukine-6 [IL-6]), and apoptotic indices (BCL2-associated X protein [Bax], B-cell lymphoma 2 [Bcl-2], caspase-3)], against GEM-induced nephrotoxicity in rats. Materials and Methods: Thirty adult male Wistar rats were allocated to five groups. Positive control and treatment groups were given GEM to induce nephrotoxicity. Animal treatment groups were treated with camphor in olive oil for 12 days. Renal biopsies, serum, extraction of renal tissue and urine of rats were taken after the twelfth day. Biopsies were examined for structural changes using a light microscope, moreover, apoptosis, desired biochemical and inflammatory factors, were investigated by suitable methods. Results: Camphor had no effect on biochemical factors, including malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), urea, creatinine and urine protein. However, it reduced the gene expression of TNF-α, NF-κB, IL-6, Bax, and caspase-3 and increased the gene expression of GPX and CAT and Bcl-2. Moreover, camphor improved kidney histopathological changes in the camphor groups in comparison with the GEM group. Conclusion: Camphor can be useful in the attenuation of GEM-induced nephrotoxicity based on expression levels of examined enzymes and factors and improving kidney histopathological changes.

TNF-α inhibits SP-A gene expression in lung epithelial cells via p38 MAPK

2002 ◽  
Vol 283 (2) ◽  
pp. L418-L427 ◽  
Author(s):  
Olga L. Miakotina ◽  
Jeanne M. Snyder
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tnf Α ◽  
Lung Epithelial

Surfactant protein A (SP-A), the major lung surfactant-associated protein, mediates local defense against pathogens and modulates inflammation in the alveolus. Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, inhibits SP-A gene expression in lung epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase pathway, i.e., wortmannin, LY-294002, and rapamycin, did not block the inhibitory effects of TNF-α on SP-A mRNA levels. An inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, PD-98059, was also ineffective. PD-169316 and SB-203580, inhibitors of p38 MAPK, blocked the TNF-α-mediated inhibition of SP-A mRNA levels. TNF-α increased the phosphorylation of p38 MAPK within 15 min. Anisomycin, an activator of p38 MAPK, increased p38 MAPK phosphorylation and decreased SP-A mRNA levels in a dose-dependent manner. Finally, TNF-α increased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNF-α downregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.

scholarly journals Acetylcholine Attenuated TNF-α-Induced Apoptosis in H9c2 Cells: Role of Calpain and the p38-MAPK Pathway

2015 ◽  
Vol 36 (5) ◽  
pp. 1877-1889 ◽  
Author(s):  
Ming Zhao ◽  
Yang Yang ◽  
Xueyuan Bi ◽  
Xiaojiang Yu ◽  
Hanghuan Jia ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Calpain Inhibitor ◽  
Mapk Phosphorylation ◽  
Tnf Α ◽  
Expression And Activity

Background: Previous studies have shown that inflammation is associated with excessive activation of calpains. Acetylcholine (ACh) has been reported to inhibit pro-inflammatory cytokine release and protect against cardiomyocyte injury. However, there is no direct evidence regarding whether ACh can regulate calpains to exert cardioprotection. To this end, we investigated the effect of ACh on tumour necrosis factor alpha (TNF-α)-induced cardiomyocyte injury and further explored the underlying mechanism. Methods: Flow cytometry and transmission electron microscopy were performed to evaluate apoptosis and cellular ultrastructure. Western blotting was performed to assess changes in protein expression. siRNA was employed to silence specific proteins. Results: TNF-α treatment increased the expression of cleaved caspase-3, calpain-1 and p38-mitogen-activated protein kinase (p38-MAPK). The calpain inhibitor PD150606 and the p38-MAPK inhibitor SB203580 inhibited apoptosis induced by TNF-α. Moreover, SB203580 decreased the expression and activity of calpain-1, possibly related to the up-regulation of calpastatin. ACh significantly inhibited TNF-α-induced cell apoptosis, as evidenced by decreases in caspase-3 cleavage, p38-MAPK phosphorylation, and calpain-1 expression and activity as well as increases in calpastatin expression. These beneficial effects of ACh were abolished by atropine or M2AChR siRNA. Conclusion: Our results suggest that ACh ameliorated TNF-α-induced calpain activation by decreasing p38-MAPK phosphorylation and enhancing calpastatin expression, indicating that calpain may be an important link between inflammatory factors and myocardial cell apoptosis.

scholarly journals Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 653
Author(s):  
Seth O. Asiedu ◽  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Michael D. Wilson
Keyword(s):  
Molecular Docking ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Computational Techniques ◽  
Cytokine Storm ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

scholarly journals Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 540-552 ◽  
Author(s):  
Hany H. Arab ◽  
Samir A. Salama ◽  
Tamer M. Abdelghany ◽  
Hany A. Omar ◽  
El-Shaimaa A. Arafa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mapk Pathway ◽  
Lipid Peroxide ◽  
Mitogen Activated Protein Kinase ◽  
Camel Milk ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Anti Oxidant ◽  
Cox 2 ◽  
Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

TNF-α and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms

2001 ◽  
Vol 281 (6) ◽  
pp. G1405-G1412 ◽  
Author(s):  
T. Suzuki ◽  
E. Grand ◽  
C. Bowman ◽  
J. L. Merchant ◽  
A. Todisco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
G Cells ◽  
Kinase C ◽  
Tnf Α ◽  
Mitogen Activated Protein

Helicobacter pyloriand proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-α and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-α and IL-1 significantly increased gastrin mRNA in canine G cells to 181 ± 18% and 187 ± 28% of control, respectively, after 24 h of treatment. TNF-α and IL-1 stimulated gastrin promoter activity to a maximal level of 285 ± 12% and 415 ± 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-α and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.

Study of the antineoplastic effect of modulating apoptosis-related noncoding RNA in human hepatocellular carcinoma cell line (HepG2)

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mai Abdel Azeem Sherif ◽  
Emtiaz Abd-elkawy Ismail ◽  
Samar Kamal Kassim ◽  
Hanan Hussein Shehata ◽  
Marwa Ali Abdel Khalek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Noncoding Rna ◽  
Caspase 3 ◽  
Control Group ◽  
Antineoplastic Effect ◽  
And Control ◽  
Hcc Cells ◽  
Liver Tissues

Abstract MiR-421 is considered an important molecule that can prevent tumor growth. Bioinformatics analysis indicated that mRNA caspase-3 gene is a target gene of miR-421. The current study aimed to explore the functional role of miR-421 in hepatocellular carcinoma (HCC) and explore the interaction between miR-421 and caspase-3. To validate bioinformatics data, RT-qPCR was used to detect the expression of miR-421 and caspase-3 in 10 HCC tissues. The results showed miR-421 expression was significantly higher in HCC than non HCC liver tissues (P<0.01), nevertheless caspase-3 gene expression was markedly lower in HCC than non HCC liver tissues (P<0.01). Besides, miR-421 expression was negatively associated with caspase-3 expression. MiR-421 mimic and inhibitor was transfected into HCC cell lines (HepG2). Proliferation assay, showed that low-expression of miR-421 inhibited the proliferation of HCC cells. RT-qPCR was worked for detection the expression levels of miR-421 and caspase-3 in HepG2 cells before and after transfection. The results showed that miR-421 expression in HepG2 cells was significantly lower in miR-421 inhibitor transfected group than in mimic- transfected and control groups (Mock) (P≤ 0.05), and caspase-3 gene expression in HCC tissues was markedly higher in inhibitor transfected group than those transfected by mimic and control group (Mock) (P≤0.05). Thus, miR-421 inhibitor may inhibit the proliferation of HCC cells via over- expression of caspase-3.

scholarly journals Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway

2019 ◽  
Vol 20 (14) ◽  
pp. 3574 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Bu-Yeo Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Mrna Expression ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mice Model ◽  
Tnf Α ◽  
Cox 2

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.

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